Collagenase has been used for years in the debridement of burns, which involve collagen, and various ulcers, which comprise mixed fibrin clots. The collagenase acts to remove the undesired tissue and thus promote the healing of the lesion. The greater the speed at which the debridement takes place the sooner will the wound heal. Thus speed of debridement is a prime consideratum.
We have discovered that if collagenase is applied to the wound in combination with a phosphatidylcholine (hereinafter termed “PC”) of which lecithin is a readily available source, and an organogel a surprising increase in the speed of debridement results. Lecithin organogels have been used in the past in combination with drugs, such as non-steroidal anti-inflammatories, anesthetics, hormones, steroids and anti-histamines, in order to enable the drugs to be applied topically and readily pass through normal skin and enter the bloodstream. Debridement, however, involves treatment of tissue other than skin, and the wound-debridement effect of collagenase is significantly different from the topical or transdermal delivery of drugs to the system because entry of the collagenase into the bloodstream, to the extent that it might occur, is not a factor.
We have discovered that a combination of collagenase with an organogel including PC, such as a lecithin organogel, when applied to lesions of the type here discussed, gives rise to a surprisingly rapid debridement significantly superior to the debridement effect of other collagenase preparations. (Because of the ready availability of lecithin as a source of PC we will for the most part use the term “lecithin” to refer generically to any source of PC as well as specifically to those complex substances to which the term is normally applied.)
Institutions where burns are treated, such as hospitals and in particular burn centers where burn treatment is the rule and not the exception, must maintain on the shelf adequate supplies of collagenase, so as to be ready to treat burn cases as soon as they are presented, in order both to speed healing and minimize pain. It therefore is essential that the collagenase standing on the shelf waiting to be used should have as long a shelf life as possible. However, it is well known that certain collagenase compositions which are quite satisfactory when first prepared find their potency waning significantly with time. In particular, combinations of collagenase with water or aqueous excipients, while therapeutically highly acceptable, nevertheless have a shelf life at room temperatures of two weeks or less, which makes them unsatisfactory.
The PC (lecithin) organogels useful in the present invention may contain water. In patent application Ser. No. 10/094,226, filed Mar. 11, 2002, and titled “METHOD OF ENHANCING THE EFFECT OF COLLAGENASE ON WOUNDS” some of us have disclosed that the shelf life problem presented by aqueous collagenase mixtures, which are very effective in debridement, can be overcome by starting with a first substance comprising collagenase in a non-aqueous excipient and a separate second substance comprising an aqueous excipient, the two substances being combined at the time of application to produce an improved and surprisingly rapid treatment effect as compared with applying the collagenase to the wound in a non-aqueous excipient or in an aqueous excipient alone. The advantages of that approach to the use of collagenase are also obtainable in connection with the present invention when the collagenase is initially combined with lecithin and an organic solvent to produce a non-aqueous phase and when the gel-forming agent is initially combined with water to produce an aqueous phase, the two phases being separately stored and each having an effective shelf life, the two phases being mixed together shortly prior to application to the wound.
It therefore is the prime object of the present invention to combine collagen with a substance which enhances the collagen's normal debridement effect, and to do so through the use of readily available ingredients and in a manner which enables the components when stored to have an adequate shelf life.